An autosomal dominant locus, Nka, mapping to the Ly-49 region of a rat natural killer (NK) gene complex, controls NK cell lysis of allogeneic lymphocytes
An autosomal dominant locus, Nka, mapping to the Ly-49 region of a rat natural killer (NK) gene complex, controls NK cell lysis of allogeneic lymphocytes
复制标题
DOI：
10.1084/jem.183.5.2197
复制
发表时间：
1996-05-01
影响因子：
15.3
通讯作者：
Fossum, S
中科院分区：
文献类型：
--
作者：
Dissen, E;Ryan, JC;Fossum, S
自然杀伤（NK）细胞可以识别和杀死MHC不相容的正常骨髓来源的细胞。目前表征的NK细胞上的MHC结合受体，包括小鼠中的Ly-49家族，在与同源的I类MHC配体结合后传递抑制信号。在这里，我们研究在体内NK细胞介导的溶解正常异基因淋巴细胞之间的交叉反应能力的PVG大鼠和变应性缺陷的DA大鼠。来自两种菌株的NK细胞能够裂解标准肿瘤靶标。我们确定了一个常染色体显性基因座，Nka，控制NK介导的同种异体反应性。携带显性PVG等位基因的个体在单次给药中完全有能力消除同种异体靶细胞，这表明Nka编码或调节诱导或激活同种异体反应性的基因产物。通过连锁分析和脉冲场凝胶电泳，大鼠4号染色体上的自然杀伤基因复合体（NKC）的描述，包含大鼠NKR-P1和Ly-49多基因家族加上大鼠NKG 2D同源。Nka图谱在NKC内，与大多数端粒Ly-49家族成员一起，但与NKG 2D和NKR-P1家族分开。此外，Nka编码的应答与NK细胞群体中Ly-49受体的转录物的表达相关，因为北方印迹分析表明，与在变应性感受态PVG、（DA X PVG）F-1和PVG.1AV1 NK细胞中的高表达相反，在DA NK细胞中Ly-49基因的低表达。DA中Ly-49的低表达不是由MHC单倍型诱导的，如在DA MHC同源PVG.1AV1菌株中Ly-49的高表达所证明的。最后，我们已经克隆并表征了大鼠Ly-49基因家族的前四个成员。它们的胞质结构域表现出很大的异质性，这与不同的Ly-49家族成员可能具有不同的信号传导功能的假设一致。
Natural Killer (NK) cells can recognize and kill MHC-incompatible normal bone marrow-derived cells. Presently characterized MHC-binding receptors on NK cells, including the Ly-49 family in the mouse, transmit inhibitory signals upon binding to cognate: class I MHC ligands. Here we study in vivo NK-mediated lysis of normal allogeneic lymphocytes in crosses between alloreactivity-competent PVG rats and alloreactivity-deficient DA rats. NK cells from both strains are able to lyse standard tumor targets. We identify an autosomal dominant locus, Nka, that controls NK-mediated alloreactivity. Individuals carrying the dominant PVG allele in single dose were fully competent in eliminating allogeneic target cells, suggesting that Nka encodes or regulates a gene product inducing or activating alloreactivity. By linkage analysis and pulsed field gel electrophoresis, a natural killer gene complex (NKC) on rat chromosome 4 is described that contains the rat NKR-P1 and Ly-49 multigene families plus a rat NKG2D homologue. Nka maps within the NKC, together with the most telomeric Ly-49 family members, but separate from NKG2D and the NKR-P1 family. The Nka-encoded response, moreover, correlates with the expression of transcripts for Ly-49 receptors in NK cell populations, as Northern blot analysis demonstrated low expression of Ly-49 genes in DA NK cells, in contrast to high expression in alloreactivity-competent PVG, (DA X PVG)F-1, and PVG.1AV1 NK cells. The low Ly-49 expression in DA is not induced by MHC haplotype, as demonstrated by high expression of Ly-49 in the DA MHC-congenic PVG.1AV1 strain. Finally, we have cloned and characterized the first four members of the rat Ly-49 gene family. Their cytoplasmic domains demonstrate substantial heterogeneity, consistent with the hypothesis that different Ly-49 family members may subserve different signaling functions.